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IRG1/itaconate rewires macrophage and lung tumor metabolism through G6PD inhibition

Tumor-associated macrophages (TAMs) possess both tumor-promoting and tumor-inhibiting roles. Here, we explore TAMs’ anti-tumor functions, focusing on the immune responsive gene 1 (IRG1) and its product, itaconate, in lung cancer development. Spatial metabolomics reveals that endogenous itaconate is...

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Autores principales: Mansouri, Siavash (Autor) , Hesami, Golnaz (Autor) , Ambikan, Anoop (Autor) , Karger, Annika (Autor) , Klatt, Stephan (Autor) , Neogi, Ujjwal (Autor) , Kurakula, Konda Babu (Autor) , Aliraj, Blerina (Autor) , Miller, Anne (Autor) , Petrova, Boryana (Autor) , Sanda, Miloslav (Autor) , Sirait-Fischer, Evelyn (Autor) , Guenther, Stefan (Autor) , Kuenne, Carsten (Autor) , Ruppert, Clemens (Autor) , Alkoudmani, Ibrahim (Autor) , Gattenlöhner, Stefan (Autor) , Zukunft, Sven (Autor) , Fleming, Ingrid (Autor) , Haschemi, Arvand (Autor) , Stiewe, Thorsten (Autor) , Grimminger, Friedrich (Autor) , Reck, Martin (Autor) , Weigert, Andreas (Autor) , Seeger, Werner (Autor) , Pullamsetti, Soni Savai (Autor) , Savai, Rajkumar (Autor)
Formato: Article (Journal)
Lenguaje:inglés
Publicado: 7 July 2026
In: Cell metabolism
Year: 2026, Volumen: 38, Número: 7
ISSN:1932-7420
DOI:10.1016/j.cmet.2026.05.005
Acceso en línea:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.cmet.2026.05.005
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1550413126001907
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Notas de Autor:Siavash Mansouri, Golnaz Hesami, Anoop Ambikan, Annika Karger, Stephan Klatt, Ujjwal Neogi, Konda Babu Kurakula, Blerina Aliraj, Anne Miller, Boryana Petrova, Miloslav Sanda, Evelyn Sirait-Fischer, Stefan Guenther, Carsten Kuenne, Clemens Ruppert, Ibrahim Alkoudmani, Stefan Gattenlöhner, Sven Zukunft, Ingrid Fleming, Arvand Haschemi, Thorsten Stiewe, Friedrich Grimminger, Martin Reck, Andreas Weigert, Werner Seeger, Soni Savai Pullamsetti and Rajkumar Savai
Descripción
Sumario:Tumor-associated macrophages (TAMs) possess both tumor-promoting and tumor-inhibiting roles. Here, we explore TAMs’ anti-tumor functions, focusing on the immune responsive gene 1 (IRG1) and its product, itaconate, in lung cancer development. Spatial metabolomics reveals that endogenous itaconate is markedly depleted within lung tumor regions compared with adjacent non-tumor tissue. Single-cell RNA sequencing shows that macrophages are the primary cells expressing IRG1 in human and mouse lung tumors. Both IRG1 knockout and transplantation of IRG1-depleted bone marrow leads to increased lung tumor growth in various mouse lung tumor models. Additionally, 4-octyl itaconate (Octyl Ita) reduces tumor growth in vitro, in vivo, and in ex vivo human tumor precision-cut lung slices. An integrated multi-omics analysis shows that IRG1/itaconate causes a metabolic shift in cancer cell and pro-tumor macrophages, mainly by inhibiting the pentose phosphate pathway (PPP) through targeting glucose-6-phosphate dehydrogenase (G6PD) activity, thereby suppressing cancer cell growth and transforming pro-tumor macrophages into anti-tumor macrophages. Thus, leveraging IRG1/itaconate’s tumor-suppressive effects or using Octyl Ita could be a novel lung cancer therapy.
Notas:Online verfügbar: 3. Juni 2026, Artikelversion: 7. Juli 2026
Gesehen am 10.08.2026
Descripción Física:Online Resource
ISSN:1932-7420
DOI:10.1016/j.cmet.2026.05.005

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